Telomerase is a ribonucleoprotein that catalyzes the addition of telomeric repeats to the ends of telomeres. Telomeres are long stretches of repeated sequences that cap the ends of chromosomes and are believed to stabilize the chromosome. In humans, telomeres are typically 7-10 kb in length and comprise multiple repeats of the sequence -TTAGGG-. Telomerase is not expressed in most adult cells, and telomere length decreases with successive rounds of replication. After a certain number of rounds of replication, the progressive shortening of the telomeres results in the cells entering a telomeric crisis stage, which in turn leads to cellular senescence. Certain diseases are associated with rapid telomeric loss, resulting in premature cell senescence. Expression of the gene encoding the human telomerase protein in human cells has been shown to confer an immortal phenotype, presumably through bypassing the cells' natural senescence pathway. In addition, expression of the telomerase gene in aging cells with short telomeres has been shown to produce an increase in telomere length and restore a phenotype typically associated with younger cells.
Somatic cells, in contrast to tumor cells and certain stem cells, have little or no telomerase activity and stop dividing when the telomeric ends of at least some chromosomes have been shortened to a critical length, leading to programmed cellular senescence (cell death). Since the loss of telomeric repeats in somatic cells, leading to senescence, is augmented by low telomerase activity, induction of telomerase activity, which has the effect of adding arrays of telomeric repeats to telomeres, thereby imparts to mortal somatic cells increased replicative capacity, and imparts to senescent cells the ability to proliferate and appropriately exit the cell cycle upon repair of damaged tissue.
Methods of increasing telomerase activity therapeutically have been investigated by, for example, Bodnar Science 279(5349):349-52 (Jan. 16, 1998)); White, PCT Int. Appl. Pubn. No. WO 2000/08135 (February 2000)); Hannon et al. PCT Int. Appl. Pubn. WO 99/35243 (July 1999) and PCT Int. Appl. Pubn. No. WO 2000/031238 (June 2000)); Franzese et al. Lifescience 69(13) 1509-20 (2001), and Yudoh et al. J. Bone and Mineral Res. 16(8):1453-1464 (2001). In these reports, telomerase activity is generally increased by overexpression of hTERT, the gene encoding the protein component of human telomerase, or by expression of proteins which mediate assembly of telomerase, e.g. heat shock proteins (White, PCT No. WO2000/08135). Franzese et al. reported that Saquinavir, a protease inhibitor prescribed for treatment of HIV infection, increased telomerase activity in peripheral blood mononuclear cells; Vasa et al. Circ Res. 87(7) 540-2 (2000) described activation of telomerase, and a resulting delay in endothelial senescence, by administration of a nitric oxide (NO) precursor.
Various saponins of the astragalo side family have been reported as having various biological effects including increasing telomerase activity, Harley et al. PCT Int Appl. Pubn. No. WO2005/000245. It would be beneficial to develop a compound which was an effective telomerase activator.